Advances in Alzheimer's Disease

Clinical Review

Advances in Alzheimer’s Disease A Review for the Family Physician

Man? Elizabeth Roth, M l), MSA Southfield, Michigan

Alzheimer’s disease accounts for approximately two disease involves a two-pronged approach: behavioral- thirds of all cases o f dementia in the United States and supportive care and pharmacologic control o f disrup S90 billion in health care costs annually. Clinical and tive behavioral symptoms. In the future, drug therapy laboratory diagnostic tools have been refined so that may be available to maintain memory and cognitive clinicians now can diagnose Alzheimer’s disease with function. Cholinesterase inhibitors, which block the de up to 90% accuracy. Criteria for clinical diagnosis have crease in choline acetvltransferasc activity associated been outlined by a work group o f the National Insti with Alzheimer’s disease, appear promising. The realis tute of Neurological and Communicative Disorders tic goal of health care providers at the present time, and Stroke and the Alzheimer’s Disease and Related however, should be symptom control rather than dis Disorders Association. Key diagnostic tools include a ease reversal. complete patient history', mental status testing, and a thorough diagnostic workup to exclude the possibility' Key words. Alzheimer’s disease; dementia; patient care- of a reversible disease mimicking the symptoms of Alz planning; cholinesterase inhibitors. (/ ham Pract 1993; heimer’s disease. Currently, management of Alzheimer’s 37:593-607)

Alzheimer’s disease is one o f the most ironic and tragic among unaffected subjects of the same age, and it has consequences o f modern medicine’s success in prolong been suggested that the disease has become the third or ing survival until the 7th, 8th, and even 9th decade ot fourth ranking cause of death (usually resulting from life. Family physicians can expect to encounter this re pneumonia)2 among people between the ages of 75 and lentless and debilitating disorder in an estimated 1 of 85 vears.3 Alzheimer’s disease has now emerged as the leading 1000 patients aged 60 to 65 years of age, in 4 of 100 cause of dementia before and after age 65 years, account patients over 65 years o f age, and in as many as half ot ing for two thirds of all cases o f dementia. As such, its patients over 85 years of age.1 public health impact is enormous. Alzheimer’s disease In personal terms, Alzheimer’s disease spells devas affects approximately 4 million people and is the most tation for patient and family. Its course is characterized common reason for admitting someone to a nursing by worsening memory loss and personality changes home in the United States.3-5 According to one widely (sometimes including psychotic behavior), progressing cited analysis performed in 1987, the annual costs for a to global confusion, and ultimately, to complete cogni family to care for a patient with Alzheimer’s disease- tive disintegration. The death rate among patients with amount to over $18,0006; the annual bill for the nation Alzheimer’s disease is two to four times greater than that as a whole has now reached $90 billion.4 As the US population ages, the financial and human toll o f Alzhei

Submitted, revised, August 5, 1993. mer’s disease will continue to increase. Many clinicians regard the diagnosis and manage From the Department o f Family Practice and the Geriatric Programs, Providence Medical Centers, Southfield, Michigan. Requests for reprints should he addressed to ment o f dementia with frustration, if not fatalism. Such Maty Elizabeth Roth, M D, Chairman, Department of Family Practice, 222, ( an attitude, however, is unwarranted. First, dementia Pmndencc Drive, Southfield, M I 48075.

may stem from any o f a number of medically or surgically Table 1. Brain Changes in Alzheimer’s-Tvpe Dementia correctable conditions unrelated to Alzheimer’s disease. Compared With Normal Aging Process Since the cognitive impairment associated with these Alzheimer’s-Type Dementia Normal Aging conditions is only reversible if identified and treated • Senile plaques throughout the • Senile plaques absent or early,7 a thorough diagnostic workup is always required general cortex scanty in patients with suspected Alzheimer’s disease. Second, although there is still no pharmacologic “quick fix” for • Large numbers o f neurofibrillar)' • Neurofibrillar)' tangles absent tangles in medial temporal Alzheimer’s disease, recent research has sparked the de or scant)'; if present, usuallv structures, including the confined to the hippocampus velopment of promising new drugs that may help reverse hippocampus; also frequently or slow memory loss and cognitive impairment. Alzhei present in the general cortex mer’s disease is one of several currently irreversible de • Granulovacuolar degeneration • Much less frequent mentias and requires precise diagnosis. As with many and Hirano bodies in other chronic disorders of older patients, reasonable ther hippocampus frequent apeutic goals are improvement, control, or slowing of • Severe cholinergic deficit present • Absent progression, rather than cure. Newly available therapies, including behavioral, environmental, and pharmacologic • Marked reduction of brain • 7 % - 10% reduction of brain weight: brains from patients weight by the 9th decade approaches, may permit a more active and optimistic with Alzheimer’s-type dementia approach to the management o f Alzheimer’s disease. weigh ± 10% —15% less than New therapies may even alter the clinical course of Alz those from age-matched nondemented persons heimer’s disease if the disorder can be diagnosed and N ote: The important feature is that the brain changes in Alzheimer’s-type dementia treated early. appear in combination and profusion. This review provides a summary of the most current Reprinted with permission from Van der Cammcn TJM. Diagnostic approaches and management aspects o f early dementia. Delft, Netherlands: Eburon Publishers, 1991. research regarding the causes, diagnosis, and manage ment o f the disease, and potential therapies that may be used to treat Alzheimer’s disease. more typical changes found in Alzheimer’s-type dementia contrast with changes observed during the normal aging process (Table 1). What Causes Alzheimer’s Disease? Neurochemical Alterations Histopathologic Features A good correlation exists between the histopathological It was 85 years ago that Alois Alzheimer first published changes, neurochemical abnormalities, and some cogni his classic description o f cerebral cortical changes in a tive and memory deficits found in patients with Alzhei middle-aged woman who had died with progressive de mer’s disease. For example, loss o f neurons from the basal mentia. Alzheimer’s findings are still the defining patho nucleus of Meynert has been associated with a concom logic features o f the disease that now bears his name. itant decrease in cholinergic function, and this decrease in Changes found in all patients with Alzheimer’s dis cholinergic function has been linked to memory dysfunc ease include neurofibrillary tangles (tangles of fibers); tion. neuritic plaques (clusters of degenerating nerve endings); The above relationship, termed the cholinergic hypoth widespread, nonuniform atrophy o f the brain; and loss o f esis o f memory dysfunction, theorizes that changes in predominately large neurons and synapses.5 Cell loss, cholinergic activity occur in the brains o f patients with plaques, and tangles regularly occur in the neocortex dementia, and that these changes play an important role (especially the association areas) and the hippocampus. in contributing to the memory loss and cognitive prob Loss of cholinergic neurons from the basal nucleus of lems seen in patients with Alzheimer’s disease. Thus, it Mcyncrt is a common finding. A less common finding is follows that improvement of cholinergic function by the loss of serotonergic neurons from the dorsal segmen drugs that enhance cholinergic transmission should also tal nuclei, and noradrenergic neurons from the locus improve some of the symptoms of dementia. The evi serialize.8 Conversely, the primary motor, somatosen dence in support o f a cholinergic involvement in Alzhei sory, and visual cornices tend to be spared.1 In addition, mer’s disease follows. the brains of patients with Alzheimer’s disease weigh Choline acctyltransferase (CAT) is the enzyme re some 10% to 15% less than those of age-matched con sponsible for the formation of the ncurotransmittcr ace trols. There is some overlap, however, since with normal tylcholine. Autopsy analysis o f the brains o f patients with aging the brain atrophies and decreases in weight.5 The Alzheimer’s disease show a 40% to 90% reduction in

594 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease Roth

CAT activity in the cerebral cortex and hippocampus,5 reduction in cortical somatostatin.12 Still to be deter brain areas traditionally associated with learning. This mined is whether changes in these neurotransmitter sys decrease in CAT activity is considered one of the chief tems contribute to cognitive impairment and how.11 biochemical hallmarks o f Alzheimer’s disease and corre The presence of neurofibrillary tangles and neuritic lates well with the degeneration o f neurons originating in plaques consisting of a core of excess /3-amvloid peptide the basal nucleus o f Meynert and projecting into the (28 to 43 amino acids) have been identified earlv in the hippocampus and cortex.9 The loss o f CAT, which be course of Alzheimer’s disease, and both the presence of gins as early as the first year o f Alzheimer’s disease,5 is far neurofibrillary tangles and the density of plaques appear more severe and consistent than the cholinergic deficit to correlate with the onset of dementia.13 The /3-amyloid associated with decreased muscarinic receptor density in peptide is a fragment of amyloid precursor protein, normal aging.10 In addition, some studies have revealed cleaved off excessively as a product o f protease activ ity the synthesis o f acetylcholine in biopsy samples from occurring both at the meningovascular and peripheral patients with Alzheimer’s disease to be less than that in level (particularly within platelets); /3-amvloid deposition those of age-matched controls.10 appears in patients with earlv-stage Alzheimer's disease, Evidence linking the cholinergic deficit with mem- voung people with Down's syndrome, and up to 80% of on' loss has been supported by experimentation in which the normal elderly over the age o f 80 years.13 Demon deficits in learning were produced from the destruction stration o f the direct toxicity to the neuron caused by or blockade o f cholinergic neurons.11 For example, ani /3-amyloid peptide, together with the theory of excess mal studies have shown that the surgical or pharmaco activity of proteases allow the supposition that new ther logical destruction of cholinergic neurons results in apy for Alzheimer’s disease may be focused upon devel memory impairment.9 Injections o f the anticholinergic oping protease inhibitors and tachykinin neuropeptides agent scopolamine into healthy young subjects results in to block the neurotoxicity. the development o f confusion and memory loss, resem bling the symptoms o f earlv Alzheimer’s disease.5 Similar Risk Factors effects on memory have not been observed after adren ergic or dopaminergic receptor blockade.10 Most impor There arc dozens of possible risk factors for Alzheimer’s tant, the loss o f CAT activity in patients with Alzheimer’s disease and, in practical terms, these risk factors may disease correlates well with declining cognitive function support the overall diagnostic picture in an individual as well as with the density o f ncuritic plaques and neu patient. However, the means of modifying risk factors to rofibrillary tangles.9 Similar cortical cholinergic deficits prevent Alzheimer’s disease have not yet been deter arc found in a number o f degenerative diseases that cause mined. memory loss, including Parkinson’s disease associated Although Alzheimer’s disease is not an inevitable with dementia.11 accompaniment of growing older, age is still the leading The literature supports the theory' that the cholin risk factor for Alzheimer’s disease. T he likelihood of ergic deficit in patients with Alzheimer’s disease contrib developing Alzheimer’s disease reportedly doubles every utes to their symptoms. Therefore, enhancement of 4.5 years up to the age of 9 5 .14 cholinergic activity by pharmacological manipulation Family history ranks second as a risk factor. Some may improve memory and cognitive function in these 40% of patients with Alzheimer’s disease have a close patients. Many clinical trials have suggested that cholin relative who also had the disease. It has been suggested ergic enhancers do have a beneficial therapeutic role in that there are two forms o f Alzheimer’s disease: familial the treatment o f Alzheimer’s disease. The most promis and sporadic, which is assumed to be of other than ing of these new agents will be discussed. genetic origin. Both forms seem to be identical in clinical presentation, although familial Alzheimer’s disease ap In addition to changes in cholinergic function, pa pears to have an earlier onset.15 Familial Alzheimer’s tients with Alzheimer’s disease may also show changes in disease is thought to be an autosomal dominant heredi the noradrenergic, dopaminergic, serotonergic, and so tary disorder, and studies have suggested that a gene on matostatin neurotransmitter systems. Included among chromosome 21, 19, or 14 may be involved in the these changes is neuron degeneration.9 These changes, development of Alzheimer’s disease.1-15 A connection however, are not as consistent a finding as the cholinergic that may be relevant is that patients with Down’s syn deficit.9 Some o f these changes are most striking in drome (chromosome 21 truism) who survive past the age younger patients with Alzheimer’s disease, while others of 40 years experience ncuropathologic and neurochem occur only in advanced cases o f this disease.11 Other than ical changes similar to those in patients with Alzheimer’s the cholinergic deficit, the only neurochemical abnormal disease.1-5 These changes include the development of ity that correlates with the severity oi dementia is a

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plaques and tangles, and the loss of choline acctyltrans- the Alzheimer’s Disease and Related Disorders Associa ferase in the neocortex and hippocampus in the same tion (ADRDA) has outlined criteria for clinical diagno distribution as that of typical patients with Alzheimer’s sis,20 which are summarized in Table 2. The chief diag. disease.5 Patients with Down’s syndrome produce 50% nostic criteria for Alzheimer’s disease in a patient more amyloid B/A-4 protein precursor than individuals between the ages o f 40 and 90 years are slowly progres without Down’s syndrome. Accumulations of amyloid sive memory loss and deterioration in at least two cog deposits can be found in brains of persons with Down’s nitive functions, such as language use, perception, motor syndrome in their late teens and early 20s,1 which might skills, learning ability, problem solving, abstract thought, very well represent the earliest structural abnormality yet and judgment. The impairment must be both severe detected in the brain tissues of patients with Alzheimer’s enough to interfere with normal activities and not attrib disease or Down’s syndrome.16 However, nongcnetic utable to any other illness. Other associated features mav factors also must be important, given that the majority of include a family history of dementia, plateaus in disease patients with Alzheimer’s disease have no family history progression, psychiatric symptoms (for example, alter of the disease and the concordance in identical twins is ations in mood, delusions, hallucinations, or catastrophic only 5 0 % 1 outbursts), and motor abnormalities or seizures in ad Epidemiologic studies indicate that head trauma vanced disease. On the other hand, clinicians should may be a risk factor for Alzheimer’s disease.5 It is possible suspect a disorder other than Alzheimer’s disease if the that the injury leads to loss o f neurons14 or to plaque clinical picture develops suddenly, or if the patient has formation.1 Interestingly, boxers who become “punch clouding of consciousness, focal necrologic findings, or drunk” develop neurofibrillary tangles in the cortex5'14 seizures or gait disturbances early in the course of ill besides the parkinsonian-like “dementia pugilista.” ness.20 Other suggested risk factors include being female,14 Relying solely on these clinical criteria, however, has lack of formal education,1’14 and exposure to alumi its pitfalls. Alzheimer’s disease may overlap or coexist num,17 as well as a whole host of somatic disorders with other dominating illnesses, such as multi-infarct including thyroid disease, diabetes, congestive heart fail dementia or Parkinson’s disease. Alzheimer’s disease mav ure, myocardial infarction, and vascular dementia.1’5’14 also be mimicked clinically by such uncommon nccro- logic disorders as Pick’s disease and Crcutzfeldt-Jakob disease.21 Diagnosis In addition, a small but significant percentage of systemic diseases can present as dementia.22 A partial The key questions to ask when considering the diagnosis listing of these diseases22 can be found in Table 3. of Alzheimer’s disease are “Is this patient demented?” and “It so, what is the cause?”18 The question of whether a patient’s mental state is deteriorating must, of course, be Evaluation of Patients judged in context.19 In this regard, the primary care physician who has taken care of a patient for years and is familiar with his background is in an ideal position to History identify dementia. Several studies have shown that family A careful history is the most critical part of the initial physicians arc adept at recognizing dementia, frequently evaluation. Since patients with Alzheimer’s disease are without formal mental status testing, and are quite suc often unaware of their deficits, it is particularly impor cessful at distinguishing mild to moderate dementia from tant, if possible, to obtain a corroborating history' from a the normal mental changes of aging.7 Family physicians close relative or friend. should be encouraged to inquire about the activities and First, the family physician should inquire about the functions their elderly patients can perform. patient’s most troublesome symptoms and whether these have affected daily activ ities. It must be kept in mind that Clinical Diagnostic Criteria occasional forgetfulness not accompanied by other cog nitive problems may simply represent age-associated Although a definitive diagnosis of Alzheimer’s disease- memory impairment and does not necessarily signal de can be made only by cerebral biopsy or autopsy, highly mentia.19-23 Specific questions include whether the pa specific clinical and laboratory criteria allow clinicians to tient can take care of his personal needs and household diagnose the condition with 90% accuracy.5 A working and financial responsibilities, whether he has difficulties group of the National Institute of Neurological and driving, whether he becomes easily lost or disoriented, Communicative Disorders and Stroke (NINCDS) and and whether he shows unusual irritability or agitation, or

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Table 2. Criteria for Clinical Diagnosis of Alzheimer’s Disease

I The criteria for the clinical diagnosis of PROBABLE Alzheimer’s disease include: A . Eeatures that make the diagnosis of PROBABLE Alzheimer’s dementia established by clinical examination and documented disease uncertain or unlikely include: bv the Mini-Mental Test, Blessed Dementia Scale, or some sudden, apoplectic onset- similar examination, and confirmed by neuropsychological focal neurologic findings such as hemiparesis, sensory loss, tests; visual field deficits, and incoordination early in the course deficits in two or more areas o f cognition; progressive of the illness; and seizures or gait disturbances at the onset worsening o f memory and other cognitive functions; or very early in the course of the illness. no disturbance o f consciousness; onset between ages 40 and 90, most often after age 65; \ . Clinical diagnosis of POSSIBLE Alzheimer’s disease: and absence of systemic disorders or other brain diseases may be made on the basis of the dementia svndrome, in the that in and of themselves could account for the absence of other neurologic, psychiatric, or systemic progressive deficits in memory and cognition. disorders sufficient to cause dementia, and in the presence of variations in the onset, in the presentation, or in the II. The diagnosis o f P R O B A B LE Alzheimer’s disease is supported clinical course; by: may be made in the presence of a second systemic or brain progressive deterioration o f specific cognitive functions such as disorder sufficient to produce dementia, which is not language (aphasia), motor skills (apraxia), and perception considered to be th e cause of the dementia; and should be (agnosia); used in research studies when a single, graduallv impaired activities o f daily living and altered patterns of progressive severe cognitive deficit is identified in the behavior; absence of other identifiable cause. family history' o f similar disorders, particularly if confirmed neuropathologicallv; and VI. Criteria for diagnosis of DEFINITE Alzheimer’s disease are: laboratory results of: the clinical criteria for probable Alzheimer’s disease and normal lumbar puncture as evaluated by standard histopathologic evidence obtained from a biopsy or techniques, autopsy. normal pattern or nonspecific changes in EEC , such as increased slow-wave activity, and evidence of cerebral VII. Classification of Alzheimer’s disease for research purposes atrophy on CT with progression documented bv serial should specify features that may differentiate subtypes of the observation. disorder, such as: familial occurrence; III. Other clinical features consistent with the diagnosis of onset before age of 65; PROBABLE Alzheimer’s disease, after exclusion of causes of presence of trisomy-21; and dementia other than Alzheimer's disease, include: coexistence of other relevant conditions such as Parkinson’s plateaus in the course o f progression o f the illness; disease. associated symptoms o f depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional, or physical outbursts, sexual disorders, and weight loss; other neurologic abnormalities in some patients, especially with more advanced disease and including motor signs such as increased muscle tone, myoclonus, or gait disorder; seizures in advanced disease; and CT normal for age. Reprinted with permission from M cKann G, Dutchman D, Folstein M, ct al. Clinical diagnosis o f Alzheimer’s disease: report o f the NINC.l )S-A DRDA Work Group under the auspices of Department o f Health and Hum an Sendees Task Force on Alzheimer’s disease. Neurology 1984; 34:939-43. even paranoia.19 Typically, in the early stages of Alzhei more likelv depression, a central nervous system infec mer’s disease, immediate memory—the ability to repeat tion, or a brain tumor.25 An underlying infection, or back just-learned information—tends to remain intact, metabolic or toxic cause should be suspected if the pa but the longer-term retentive memory fails.24 Seldom- tient’s consciousness is clouded. A steps decline—that is, used names o f distant acquaintances or phone numbers, periods of sudden deterioration followed by periods of for example, are likely to be forgotten. With time, the some improvement-suggests vascular (multi-infarct) de retentive memory may be so affected that a patient may mentia, particularly in a patient with a history of hyper - become unable to remember something learned a minute tension or other vascular disease.23 Other signs associated before.24 The first signs o f language impairment may be with multi-infarct dementia include hemiparesis, abnor mal gait, weakness, aphasia, and labile emotions. In older difficulties in finding the right word or forgetfulness patients, depression may accentuate the root of cognitive about names.24 impairment (so-called pseudodementia), and it is impor The next important point is to clarify' the mode of tant to look for such clues as disturbed sleep, weight loss, onset, progression, and duration of these symptoms. sadness, and negativism. Unlike patients with Alzhei Alzheimer’s disease is a chronic degenerative disease that mer’s disease, depressed patients generally do not try' to evolves gradually over many months and y'cars. In con hide their memory lapses, and they may show distress trast, if the symptoms develop over days or weeks, it is

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Table 3. Diseases That May Present as Dementia Table 4. Drugs That May Cause Central Nervous System Effects Endocrine Anemia Hypothyroidism Any cause Unpredictable CNS effects Hypoglycemia Glucocorticoids (steroids) Decreased cerebral blood flow Hypercalcemia Nonsteroidal antiinflammatory' agents Cushing’s disease Congestive heart failure H , blockers (cimetidine, ranitidine) Bradyarrhvthmias or Antihistamines Electrolyte disturbance tachyarrhythmias Decongestants Hyponatremia Cerebral emboli Hyperosmolar states Coagulopathy Predictable CNS effects Cerebral arteriosclerosis Phcnothiazines Metabolic Cranial arteritis Barbiturates Metabolic acidosis Benzodiazepines Metabolic alkalosis Infections Hepatic encephalopathy Meningovascular syphilis Metabolic toxicities Uremia General paresis Insulin Carbon dioxide narcosis Subacute bacterial endocarditis Sulfonylureas Tuberculosis Diuretics Nutritional deficiencies Acquired immunodeficiency I hiaminc (Wernicke-Korsakoft syndrome Taken incorrectly syndrome) Digoxin Vitamin B 12 Aspirin Niacin (pellagra) Adapted with permission from Winograd CH. The physician and the Alzheimer Reprinted with permission from M artin I

nosis, prognosis, and treatment of dementia are listed in over their forgetfulness.23 Yet pseudodementia may be a Table 5. Five major categories used in the assessment of major early presentation o f early cognitive loss with Alzheimer’s disease are: (1) comprehensive dementia as severe depression. All such patients need to be treated for sessment and (2) neuropsychologic tests, both used to depression as part of the evaluation for early Alzheimer’s disease. document the core characteristics o f Alzheimer’s disease; The family physician must also rule out the possi (3) global staging methods, which measure disease sever bility' that drug side effects may be causing the patient’s ity'; (4) measures o f function (eg, activities o f daily living) cognitive defects, especially in an elderly' patient on mul rating the patient’s basic ability' to function; and (5) tiple medications. Although most clinicians arc aware of assessments o f noncognitivc behavioral symptoms, which such culprits as psy'choactive and ncuroactivc drugs, opi evaluate some of the symptoms of the disease that will ates, and steroids, less obvious causes may include anti give the most trouble to families and caregivers. This list cholinergic agents, antihypertensive drugs, and digital is by no means exhaustive and is intended to provide the is.19 A partial listing of drugs26 that may cause central major scales and tests most commonly used by clinicians. nervous system effects is listed in Table 4. Finally, the Short tests recommended for use by clinicians in history should include questions about other relevant clude the Mini-Mental State Examination, the Informa diseases, trauma, surgery, psychiatric disorders, alcohol tion-Orientation-Concentration scales of the Blessed De intake, nutrition, exposure to environmental toxins, and mentia Rating Scale, and the Mattis Dementia Rating family history o f dementia, Down’s syndrome, or psychi Scale.519 The overall rate of progression of cognitive atric conditions.19 decline in patients with Alzheimer’s disease appears to be 4.1 Blessed points per y'car regardless of age of onset, duration o f illness, and family history.28 The widely used Mental Status Testing Mini-Mental State Examination,29 shown in Table 6, is a Full mental status testing characterizes the extent of brief screen for identifying deficits in orientation and cognitive impairment and can be used to confirm the memory, as well as in verbal, numerical, and spatial clinician’s impression of dementia and to follow the ability'.27-30 Its drawbacks are that it may falsely signal course of the disease. Clinicians should consider admin dementia in poorly educated patients and that it may miss istering the test themselves, if possible, so that they can very mild cases o f dementia.19-27 It is a m ini-test-not a observe the patient’s responses and moods while watch global scale. Scores on the Information-Mcmorv-Con- ing for any signs o f visual or hearing impairment.19 A centration test reportedly correlate with the number of number of multi-scale tests commonly used in the diag- cortical plaques found at autopsy and with brain CAT

598 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease R oth

Table 5. Classification of Assessment Measures of Alzheimer’s Disease ______neurological examination as well as a laboratory assess ment. A diagnostic algorithm is provided in the figure. Category Assessment Measure The differential diagnosis of Alzheimer’s disease in Comprehensive dementia Blessed (BLS) rating instruments cludes a wide spectrum of vascular, necrologic, infec assessments Mini-Mental State Examination tious, and metabolic disorders. Most important o f these (MMSE) are multi-infarct dementia, Parkinson’s disease, brain tu Mattis Dementia Rating Scale (DRS) Brief Cognitive Rating Scale (BCRS) mor, thyroid disease, neurosyphilis, and other central Alzheimer’s Disease Assessment Scale nervous system infections, and pernicious anemia.5 20 (ADAS) The human immunodeficiency virus is also a concern,

Neuropsychologic tests N YU Computerized Test Batten' and it is one that will grow as the baby boomers age. Memory Assessment Clinics Test Batten' Dementia may also be caused by renal or hepatic enceph SKT alopathy or by hypoxia or hypercapnia associated with

Global staging scales Global Deterioration Scale (GDS) pulmonary disease.19 Clinical Dementia Rating (CDR) Sensory and motor examination should be normal in the early stages o f Alzheimer’s disease, except for such Activities of daily living Katz AD L Scale (ADL) Physical-Self-Maintenance Scale (PSMS) nonspecific signs as snout reflex, jaw jerk, rigidity, or Instrumental Activities of Daily Living myoclonus.20 Signs of other dominating conditions in (IADL) clude tremor, rigidity, and bradykinesia in parkinsonism, Functional Assessment Staging (FAST) myoclonus and rigidity' in Crcutzfeldt-Jakob disease, Noncognitive, behavioral Depression flapping tremor in hepatic encephalopathy, writhing assessments Geriatric Depression Scale movements in Huntington’s chorea, focal signs and ab Dementia Mood Assessment Scale (DMAS) normal gait in multi-infarct dementia, and gait apraxia in Cornell Scale for Depression and normal pressure hydrocephalus.23 Dementia All patients with suspected Alzheimer’s disease- Behavioral Behavioral Pathology' in Alzheimer’s should have a chest radiography and an electrocardio Disease (BEHAVE-AD) gram to rule out the presence o f ischemic heart disease, Dementia Behavior Disturbance which may result in cerebral ischemia and manifest as (DBD) Scale dementia.19 Laboratory screening should include thyroid Reprinted with permission from K lugtr A Ferris SH. Scales for the assessment of Alzheimer’s disease. Psychiatr Clin North A m 1991; 14:309 26. function tests, serologic testing for syphilis and human immunodeficiency antibodies, and vitamin B 12 and foliate- determinations.5-19 Also indicated arc a complete blood deficiency.7'31 It shares the same limitations, however, as count, electrolyte panel, screening metabolic panel, uri the Mini-Mental State examination.19 nalysis, and an electrocardiogram.19 Cerebrospinal fluid O f note is the newly developed Direct Assessment of examination may' be helpful it a chronic infection is Functional Status scale, which allows assessment of func suspected.5 The electroencephalogram should be normal tional capacities that are typically affected by Alzheimer’s or may demonstrate such nonspecific signs as increased disease.32 A broad spectrum o f behaviors within seven slow-wave activity' or increased latency o f P300 poten functional categories can be measured to help evaluate tials.20 the progression o f the disease as it affects a patient’s Computed tomography scanning or magnetic reso ability to care for himself and engage in everyday activi nance imaging should be a routine part of the diagnostic ties. It can be administered in an outpatient setting, and workup of the patient with dementia.33 The computed has been found to have excellent test-retest reliabilities.32 tomography(CT) scan is invaluable for detecting such The NINCDS-ADRDA Work Group has also ad potentially treatable conditions as subdural hematoma, vocated the use o f the Hamilton Depression Scale for brain tumor, hydrocephalus, and vascular lesions. It severity o f depression; the Present State Examination for should be stressed that such disorders do not always anxiety, depression, delusions, and hallucinations; and produce focal neurologic signs.23-33 In patients with Alz heimer’s disease, CT scans may show evidence o f cerebral the Hachinski Scale for evaluating the possibility' of atrophy, but the findings are general patterns and not multi-infarct dementia.20 diagnostic criteria. Magnetic resonance imaging! M RI) is an even more sensitive scanning technique, allowing the Diagnostic Workup identification o f smaller infarcts in the brain.19-33 Care must be taken, however, to avoid misinterpreting ambig The next step is to answer the question “Is this Alzhei uous findings;thc sensitivity of M RI white matter lesions mer’s disease?” by means o f a complete physical and

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Table 6. The Mini-Mental State Examination: A Tool for Cognitive Screening of Patients with Suspected Alzheimer’s Disease

I. Orientation (Maximum score 10) Ask “W hat is today’s date?” Then ask specifically for parts omitted; eg, Date (eg, January 21) ...... 1 __ “Can you also tell me what season it is?” Year...... 2 __ Month ...... 3 Day (eg, Monday) ...... 4 Season ...... 5 ______Ask “Can you tell me the name o f this hospital?” Hospital ...... 6 __ “W hat floor are we on?” Floor ...... 7 __ “W hat town (or city) are we in?” T o w n /C ity ...... 8 __ “W hat county are we in?” County ...... 9 __ “W hat state are we in?” State ...... 10 ___

II. Registration (Maximum score 3) Ask the subject if you may test his/her memory. Then say “ball,” “flag,” “tree,” clearly and “ball” ...... 11 ___ slowly, about one second for each. After you have said all 3 words, ask subject to repeat “flag” ...... 12 ___ them. This first repetition determines the score (0-3), but keep saying them (up to 6 “tree” ...... 13 __ trials) until the subject can repeat all 3 words. If (s)he does not eventually learn all three, recall cannot be meaningfully tested. Record number o f trials: ___

III. Attention and calculation (Maximum score 5) Ask the subject to begin at 100 and count backward by 7. Stop after 5 subtractions (93, “9 3 ” ...... 14 ___ 86, 79, 72, 6 5 ). Score one point for each correct number. “8 6 ” ...... 15 ___ “7 9 ” ...... 16 ___ “7 2 ” ...... 17 ___ “6 5 ” ...... 18 ___ If the subject cannot or will not perform this task, ask him/her to spell the word “world” backwards (D, L, R, O, W). The score is one point for each correctly placed letter, eg, DLROW = 5; DLORW = 3. Record how the subject spelled “world” Number of correctly-placed backwards: ______letters ...... 19 ___ DLROW

IV. Recall (Maximum score 3) Ask the subject to recall the three words you previously asked him/her to remember “ball” ...... 20 ___ (learned in Registration) “flag” ...... 21 ___ “tree” ...... 22 ___

V. Language (Maximum score 9) Naming: Show the subject a wrist watch and ask “What is this?” Repeat for pencil. Score Watch ...... 23 ___ one point for each item named correctly. Pencil ...... 24 ___ Repetition: Ask the subject to repeat, “No ifs, ands, or buts.” Score one point for correct repetition. Repetition ...... 25 ___ 3-Stage Command: Give the subject a piece o f blank paper and saw “Take the paper in Takes in right hand ...... 26 ___ your right hand, fold it in half and put it on the floor.” Score one point for each action Folds in half...... 2 7 ___ performed correctly. Puts on floor ...... 28 ___ Reading: On a blank piece of paper, print the sentence “Close your eyes” in letters large enough for the subject to see dearly. Ask subject to read it and do what it savs. Score Closes eves ...... 29 ___ correct only if (s)he actually closes his/her eyes. Writing: Give the subject a blank piece of paper and ask him/her to write a sentence. It is to be written spontaneously. It must contain a subject and verb and make sense. Correct Writes sentence ...... 30 ___ grammar and punctuation are not necessary Copying: On a clean piece of paper, draw intersecting pentagons, each side about 1 inch, and ask subject to copy it exactly as it is. All 10 angles must be present and two must Draws p entagons...... 31 ___ intersect to score 1 point. Tremor and rotation are ignored. F.g, CP' Score: Add number of correct responses. In section III, include items 14—18 or item 19, not both. (Maximum total score 30) Total score___ Rate subject’s level o f consciousness:_____ (a) coma, (b) stupor, (c) drowsy, (d) alert

] PsycbiatrR.es 1975; 12:189-98.

600 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease Roth

Figure. Algorithm for the diagnostic workup of Alzheimer’s disease. Adapted with permission from Kokrnen E. Etiology, diagnosis, and management of dementia. Compr Ther 1989; 15:59.

has led to physicians’ overdiagnosing o f vascular demen do not exist, and the treatment for these diseases is often symptomatic rather than pathology' specific.26 tia.19’33

Supportive Care Management The family physician plays an important role in coordi nating supportive care measures with the patient s family. The management o f Alzheimer’s disease involves a three- The key to supportive care is to keep the patient social pronged approach. The first o f these is nonpharmaco- ized and mentally and physically active in a safe but logic, or essentially behavioral-supportive, care. Second stimulating environment.5’34 Some environmental aids35 is a pharmacologic control o f associated disruptive be that should provide the patient with the best possible havioral symptoms with neuroleptics, sedatives, and anx environment for him to function are listed in Table 7. iolytics. The third and newest option is the use of med Patients with Alzheimer’s disease cope best in nonstress- ication to maintain memory' and cognitive function and ful, structured, familiar, and constant surroundings. to potentially alter the course of the disease. Some memory aids35 that should be employed are listed Family physicians must remember that because a in Table 8. A useful suggestion tor patient and family specific disease is labeled terminal or progressive it docs may be to post daily schedules, pictures of family mem not mean it is not treatable. There are a number of bers, and signs that point to the location of household chronic conditions, such as diabetes mellitus, congestive objects.24 Activities that may help preserve cognitive heart failure, and degenerative arthritis, tor which cures

601 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease

Table 7. Environmental Aids for the Patient with Alzheimer’s Disease

I. Safety A. Use combination locks on doors between wards or to the outside. B. Dismantle bathroom door locks to prevent patients from locking themselves in. C. Make sure floors are not highly polished to prevent falls. D. Wipe up spills and urine immediately. E. Avoid candles and artificial fruit that can be mistaken for food. F. Adjust water temperature in faucets to avoid scalding. G. Keep medications locked up at all times. H. Have beds low to the floor. I. Have padded tongue blades visible in patients’ rooms and recreation areas for use in seizures. J. Place signs at patient’s bedside or doorway to room, indicating special care needs. K. Provide adequate light without glare. Older patients usually require extra light. L. Teach all staff members and caregivers the Heimlich method to use if patient chokes. M. Place bright tape on bottom step because of depth perception problems.

II. Stability A. Maintain consistent furniture arrangement. Make changes gradually. B. Avoid moving patient from one bed or room to another. C. Have items familiar to individual in environment and encourage their use. D. Maintain predictable daily routines. E. Take history' o f patient’s habits. Use as guide for daily activities. F. Develop long-term, consistent staff. G. Have staff members establish one-to-one relationships with patients. H. Avoid entering room suddenly, especially if room is darkened. I. Change dressings, dress and undress patients in own room or private area. J. Remove or cover large mirrors if patients become agitated by them.

III. Stimulation A. Create a cheerful environment using vibrant colors. B. Avoid use o f light blues and greens with aged patients, as they often have difficulty' seeing these colors. C. Decorate with visually stimulating objects such as posters, mobiles, pictures, and tropical fish. D. Provide large calendars and draw an X through each day to orient patients in time. Large clocks and seasonal decorations also orient patients. E. Provide bulletin boards and classes in reality' orientation. F. Use touch and eye contact as well as words to contact patients. G. Encourage visits by family, friends, children, and pets. H. Monitor radios, stereos, and TVs for noise levels. I. Remove patients from areas o f excessive noise and activity'. J. Introduce reminiscence group therapy in early phases o f disease.

IV. Freedom and Mobility' A. Provide open space so that patients are free to move around. B. Avoid light-colored tile floors with dark geometric designs; these confuse patients with faulty perception. ( Hand mitts inhibit door opening, tampering with tubes and dressings, and taking other people’s property'. Can be used instead o f restraints. D. Place photo and name of patient on door to bedroom. E. Paint bathroom and toilet doors in bright colors so that patients can identify them. F. Encourage walks as a daily activity.

Reprinted with permission from Rumside I. Nursing Care. In: Jarrik LF, Winograd CH, eds. Treatments for the Alzheimer Patient. New York, N T- Springer Publishing Company, 1988:39-58. ^

function include listening to the radio or looking at ease should not be allowed to drive, since they will newspapers or television, doing chores, attending struc experience disorientation and impairment of judgment tured social events, and participating in discussions and and reaction time, in addition to impairment of visual reminiscences.30 Engaging in physical exercise will help perception.25-36 A study o f 72 patients revealed that 30% the patient maintain body tone. Proper nutrition and had experienced at least one automobile accident since personal hygiene must be ensured as well. Supervision of the onset of dementia, and an additional 11% were meal preparation may ensure nutrition in patients who reported by caregivers to have “caused” accidents, a clear arc insensitive to time and hunger. illustration o f this potentially serious problem.36 Patients Patients past the earliest stages of Alzheimer’s dis who arc beyond the early stages o f the disease should be

602 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s D isease Roth

Table 8. Memory Aids for the Patient with Alzheimer’s Disease

(Note: Many o f these aids are appropriate for patients with or without help in the earlier phases of Alzheimer’s disease. Later thev mav have “ be done for ' hc Patlent- Others are appropriately used by caregivers at all phases of the disease. Patients should be encouraged and helped to do as much self-care as possible,) 61

I. General A. Keep pen and white, undecorated paper for reminder notes in same place for east- location. (Use black felt-tipped pen if v isual impairment exists.) B. Simplify activity schedule. C. Place easily read list o f important numbers near telephone, most used ones first. D. Keep doctor s instructions for taking medication and other health care in visible, consistent place (eg, post on wall or refrigerator door). E. Keep checklist near the usual exit door of things to be done before leaving house (eg, put keys in pocket, turn off stove, put out the cat, lock door).

II. Daily Activities A. Make a checklist o f daily activities with times in large print. Keep in visible and consistent place. B. Set alarm clock or a timer as reminder of specific things to be done. Place note by clock or timer reminding of what is to be done. C. Arrange to have a friend call at designated times to remind of an appointment. D. Establish consistent routines for important activities (eg, put morning medication near pan used to cook morning cereal).

III. Location A. Remind person o f where he or she is, or is going, and whv. B. Place signs designating important locations, such as bathroom. C. Place pictures designating function on refrigerator, stove, bathroom door. D. Keep person’s familiar, significant objects in consistent locations. E. Post list o f major items in each cupboard and drawer. E. Arrange for a friend to become familiar with objects in the home to help if they are misplaced. G. Attach eye glasses to a chain that the person can wear around the neck.

IV. Wandering A. Use identification necklace or necklace with name and address that patient cannot remove. B. Attach name and address o f patient on strips of cloth that can be put on back ol clothing with velcro. C. Alert police and neighbors to the person’s possible need for assistance in finding the way home. D. Keep card in the person’s wallet or purse or taped to jacket or hat with directions to home and name and telephone number o f responsible person. E. Enroll patient in a special registry' program where available, eg, the Los Angeles Chapter of ADRDA has instituted a special registry' and bracelet program that allows for the registry' of persons suffering from chronic memory loss. The patient will wear a bracelet with a code number, his first name, the words “Memory Loss, and a central telephone number. I he code will be registered on a computer maintained by ADRDA. F. Use structured activity programs to help reduce wandering. G. Use buddy system in institutional settings to help patients watch one another. H. Use fenced-in yards and buzzer systems to alert staff or caregivers that a patient is wandering. I. Establish a protocol for all staff members to use when patient wanders oft. J. Conduct frequent in-service classes about management of wanderers.______Reprinted with permission from Burnside I. Nursing Care. In: Jarvik IS , Winograd CH, eds. Treatments for the Alzheimer Patient. Netv York, N T: Spritzer Publishing Company, 1988:39-58.

bathrooms and electric wiring.26 Counseling the patient s prevented from traveling alone. For those beyond the family is also an important aspect of management. Stud early to middle stages, living alone without supervision ies have shown that families value being able to talk with may be impossible.25 their doctor and benefit from their doctor’s understand Patients may require close supervision to protect them from dangers ranging from falls to medication ing, support, and advice/ There is an enormous burden placed on the families errors. It may be advisable for the family to secure dan of patients with Alzheimer’s disease since family mem gerous or breakable objects. Caregivers must take into bers arc often the central caregiver. In the past, there have account the dangers posed bv unstable furniture, break been few interventional programs to help decrease the able objects, rugs that slip, stairs to be negotiated, and strain placed on family members. Recently, however, matches and gas stoves, as well as hazards posed by

603 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease ______Roth

lectures designed to increase family members’ knowledge ing depression, however, the physician should be espe of the disease and self-help groups that provide social cially careful to prescribe antidepressant drugs without support have become more common. anticholinergic activity (eg, trazodone or fluoxetine) to Patients with Alzheimer’s disease and their families avoid further compromising cognitive function.30 The require ongoing counseling from their primary care phy risks o f falls as a result o f orthostatic hypotension and the sician, starting when the disease is first suspected and possibility' o f cardiovascular toxicity must also be kept in continuing as the reality of progressive dementia and mind when tricyclic antidepressants are prescribed. The increased dependence touches the family. Families who best approach is to start with a low dose, use divided choose to provide care for patients throughout the course doses, and gradually increase the dose until the patient of the disease require access to support groups, good responds.30 As a general rule, the dose should be about clinical information about the probable course of the half that usually prescribed for younger adults.2 The disease, effective management strategies, and nonjudg- motto is “start low, go slow.”30 mcntal recommendations as to when to seek outside help Agitation. As many as one third o f patients with and nursing home placement. The Alzheimer’s Disease Aizhcimcr’s disease who have delusions, hallucinations and Related Disorders Association (ADRDA) (1-800- or aggressive agitation may improve when treated with a 272-3900) and the Area Agency on Aging (AAA) offer neuroleptic agent. However, these drugs should be used support groups and relevant literature to educate fami only to control potentially dangerous behavior and not lies. The family physician may need to provide personal to manage insomnia, fidgeting, and uncooperativencss.34 counseling and support of the caregiver(s) to prevent Clinicians should prescribe low doses o f these agents and caregiver disease (backache, exhaustion, headache, peptic should try- periodically to decrease the dose or discon reflux, and other somatic complaints) and psychological tinue the medication altogether. Caution is in order, problems (depression, anxiety, sleep disorders, substance since neuroleptics, like tricyclic antidepressants, cam' the abuse).37 Texts such as The Michigan Long-Term Care risk of anticholinergic side effects and orthostatic hy Reader review the legal, economic, and social interven potension, and in addition, may cause cxtrapyramidal tions needed to provide a protected environment for reactions such as bradykinesia, rigidity, and tremor. The patients with Alzheimer’s disease.38 higher potency neuroleptics, such as haloperidol and Adult day-care centers and respite care centers may fluphenazine, have been recommended for use in patients help the patient and relieve the family’s burden as well. with Alzheimer’s disease.22-24 Propranolol, carbamaz- The ADRDA can provide the family with information epinc, and fluoxetine have also been applied in the treat on such programs, as well as family support groups. ment of aggressive agitation in patients with dementia, Social workers may be able to provide referrals to nurs- but their value in this setting is unproven.34-40 All neu ing, physical therapy, and homcmaking services. Timely roleptics are restricted in their use in nursing home use of outsidc-the-homc day care or respite care can centers under Omnibus Budget Reconciliation Act reg reduce caregiver deterioration that could arise as a result ulations. Nonsedating anxiolytics such as an azaperone of depression, medical illness, or “burnout.” (eg, buspirone) appear promising, and their use at low There is now a movement to open special-care units doses is not restricted. within nursing homes for the care of patients with Alz Less severely agitated patients with Aizhcimcr’s dis heimer s disease or related dementia. These programs ease sometimes may be helped by a short course of take into account the security and safety measures, men benzodiazepines (eg, temazepam, triazolam), but these tal and physical stimulation, and demanding physical care drugs should not be used for more than a week at a required by patients with dementia, and provide staff time.2-34 Behavioral plans to have the patient exercise who arc trained to care for these patients.39 Guidelines adequately during the day also can aid sleeping. If the for such facilities vary greatly. Although some states have patient continues to experience difficulty sleeping, low developed licensing regulations, it is difficult to assess the doses of hydroxyzine or haloperidol may be appropriate. appropriateness of care in absolute terms since experts still disagree about precisely what good care for patients with dementia should include. It is hoped that long-term studies will be initiated to resolve these issues. Treatment of Cognitive Impairment Pharmacologic agents may play a useful but, to date, Treatment o f Psychiatric Symptoms limited role in the overall treatment of cognitive impair ment in Alzheimer’s disease. Nonetheless, these agents Depression. Depression may accompany Aizhcimcr’s dis may provide limited but positive benefits to both patients ease and can contribute to cognitive decline. When treat- and their family members. A partial list o f some of the

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Table 9. Some Drugs of Potential Benefit in Improving Cognitive Function or Slowing the Progression of shown that physostigmine is significantly better than Alzheimer’s Disease______placebo in improving memory, though not other cogni tive functions.42-43 A short-term studv found that im Augmenting acetylcholine Vascular system provements in memory correlated with increases in cen Cholinesterase inhibitors V asodilators7 tral cholinergic activity,43 thereby supporting the Physostigmine Ergoloid mesylates Tetrahvdroaminocridine Nicergoline contribution of the cholinergic deficit to memory loss. Velnacrine maleate Captopril Thus, these studies pioneered the clinical applicability of Increasing precursors Calcium channel blockers long-term cholinesterase inhibition in the management Lecithin Nimodipine of patients with Alzheimer’s disease. The half-life of Nootropics* Miscellaneous physostigmine in plasma is 30 minutes, necessitating oral Piracetam Monoamine oxidase (3 inhibitors Oxiracetam Selegiline (deprenvl) dosing even' 2 hours to achieve steady-state levels44-45— Nerve growth factor not a realistic regimen. Cell membrane stabilizers As a result, enthusiasm greeted a report that a long Phosphatidvlserine er-acting cholinesterase inhibitor, tctrahydroaminoacri- * These are drugs otherwise affecting neuron function. f Nominally vasodilators, the mechanism o f action in treating Alzheimer’s disease may dinc (THA, or tacrine), significantly improved clinical be different. and psychological performance in patients with Alzhei Modified with permission from Cooper JK . Drug treatment o f Alzheimer’s disease. Arch Intern Med 1991; 151:24-59. Copyright 1991, American Medical Association. mer’s disease.46 The results of this small study were challenged, however, when it was subsequently reported that with longer treatment deterioration o f initially im therapies34 can been found in Table 9. At present, there proved memory occurred.47 Larger studies have been is no one drug that can be used to successfully treat all of completed since. In 6 -week and 8 -week clinical trials of the symptoms associated with this debilitating disease. tacrine administered to patients with moderate to severe While some improvement in cognitive function has been Alzheimer’s disease, tacrine was found to improve cog demonstrated with several agents, it is clear that research nitive test scores but not clinical function.48-49 Patients into developing an effective pharmacologic agent is only may exhibit improved mental status testing scores for in the initial stages. memory, but show no improvement in assessments of Vasodilators. The use o f vasodilators in Alzheimer’s activities of daily living and instrumental activities of disease originated from the now discarded notion that daily living. Dosing of tacrine in protocols has ranged dementia was caused by “hardening o f the arteries.”2 The from 40 to 160 mg/d, in three to four divided doses with crgoloid mesylate compound Hydcrgine LC, formerly meals.48-49 Concern about hepatotoxicity and elevation classified as a cerebral vasodilator, is now termed a met of transaminases has precluded recommendation of the abolic enhancer, although how this action pertains to the higher levels (150 to 200 mg/d) originally tested by treatment o f dementia is uncertain. It is currently the Summers ct al.46-48' 50 The Tacrine Collaborative Study only FDA-approved drug for treatment o f Alzheimer’s Group reported in 1992 that the lower doses of tacrine disease, but it appears to be an ineffective treatment.41 (40 to 80 mg/d) administered for 6 weeks showed mar Another ergot drug, niccrgolinc, reduced disorientation ginal improvement over placebo in terms of functional in nearly a third o f patients in a multiccnter, double-blind scales,49 while the Canadian double-blind crossover mul placebo trial, but this drug is not available in the United ticcnter study, administering up to 100 mg/d, reported States.34 Nimodipinc, a calcium channel blocker selective no clinically significant improvement over an 8 -week for the brain vasculature, is now being studied in patients trial.48 The FDA approved tacrine to treat mild to mod with Alzheimer’s disease34; such therapy has the potential erate Alzheimer’s disease in 1993. Another cholinesterase inhibitor currently under to improve local oxygenation, although its present cost clinical investigation for its effect on memory and cogni may limit its use. tion is vclnacrinc maleatc. This new cholinesterase inhib Cholinergic enhancers. The cholinergic enhancers rep itor has been shown to be as effective as tacrine in resent the first real therapeutic option for treating mem reversing scopolamine-induced dementia in animal mod ory loss and cognitive dysfunction for patients with Alz els.51 Clinical studies arc currently under way investigat heimer’s disease. They should be considered the first ing the effect of vclnacrinc maleatc on memory and rational therapy for Alzheimer’s disease, since they ad cognition in patients with Alzheimer s disease. dress a known underlying ncurochemical abnormality. The pharmacokinetic profile o f vclnacrinc maleatc The most successful cholinergic enhancers to date have indicates that it is quickly absorbed in both young and been the cholinesterase inhibitors, which block the en elderly subjects after oral administration, reaching peak zyme that degrades acetylcholine. The prototype cholin plasma concentrations in 0.9 to 1.7 hours53; its bioavail- esterase inhibitor is physostigmine. Long-term trials have

605 The Journal of Family Practice, Vol. 37, No. 6, 1993 Alzheimer’s Disease

ability is not changed by food, an important practical physicians have been admonished not to rush to the issue with a drug that must be taken on a long-term diagnosis of Alzheimer’s disease, as there was no specific basis.54 In elderly patients, vclnacrinc has a 2- to 3-hour recommendation for therapy and treatment. This trend half-life; between 11% and 30% of a given dose is may soon be reversed. excreted unchanged in the urine, and the drug is elimi nated quickly over all dosage ranges.53 55 Other agents. Numerous theories as to the patho Acknowledgment physiologic origins of Alzheimer’s disease have been posed, and, over the years, many drugs have been tested Supported by an educational grant from Hoechst-Roussel Pharmaceu ticals, Inc. in animal studies and a few have reached preliminary human studies. Lecithin, ergoloid mesylates, and vasodi lators are among the oldest agents tried in double-blind crossover human studies, but none have resulted in sta References tistically significant improvement in patients with Alzhei 1. Katzman R, Saitoh T. Advances in Alzheimer’s disease FASEB1 mer’s disease. Recent studies with L-deprenyl, a 1991; 5:278-86. monoamine-oxidase inhibitory drug used successfully to 2. Hutton JT. Alzheimer’s disease: evolving clinical concepts and management strategies. Cornpr Ther 1987; 13:55-64. treat Parkinson’s disease, show no measureablc impact on 3. Weiler PG. The public health impact of Alzheimer’s disease Am] cognitive or behavior function in patients with Alzhei Public Health 1987; 77:1157-8. mer’s disease.56 Current research has focused on inhibit 4. Information sheet. Chicago, 111: The Alzheimer’s Disease and Related Disorders Association, Inc, 1991. ing the formation o f neurofibrillary tangles at a biochem 5. Katzman R. Alzheimer’s disease. N Engl J Med 1986 - 314-964- ical level. T o date, no drug has been uniformly successful. 73. 6. Hay JW , Ernst RL. The economic costs of Alzheimer’s disease. Am J Public Health 1987; 77:1169-75. 7. Van der Cammen TJM. Diagnostic approaches and management aspects of early dementia. Delft, Netherlands: Eburon Publishers Conclusions 1991. 8. Katzman R, Brown T, Fuld P, Thai L, Davies P, Terry R. Signif Until the underlying causes o f nerve cell degeneration in icance of neurotransmitter abnormalities in Alzheimer’s disease. Alzheimer’s disease can be unraveled and therapeutically In: Martin JB, Barchas JD , eds. Neuropeptides in neurologic and targeted, management can aspire only to symptom con psychiatric disease. New York, NY: Raven Press, 1986:279-86. 9. Bartus RT, Dean RL, Pontecorvo MJ, Flicker C. The cholinergic trol, rather than disease reversal. At present, this can be hypothesis: a historical overview, current perspective, and future accomplished by a variety of behavioral, environmental, directions. Ann NY Acad Sci 1985; 444:332-58. and perhaps in the near future, pharmacologic interven 10. Bartus RT, Dean RL, Beer B, I -ippa AS. The cholinergic hypoth esis of geriatric memory dysfunction. Science 1982; 217:408-17. tion. Cholinesterase inhibitors such as vclnacrinc malcate 11. Perry E. Acetylcholine and Alzheimer’s disease. Br J Psvchiatrv and tacrine show some promise as a strategy for slowing 1988; 152:737-40. the memory loss and cognitive impairment of this dis 12. Rossor M, Iversen LL. Non-cholinergic neurotransmitter abnor malities in Alzheimer’s disease. Br Med Bull 1986; 4 2 :7 0 -4 . abling disease and may produce modest improvement in 13. Yankner BA, Mesulam M-M./3-amyloid and the pathogenesis of selected patients. Alzheimer’s disease. N Engl J Med 1991; 325:1849-57. There is a clear need for further investigation of the 14. Henderson AS. The risk factors for Alzheimer’s disease: a review and a hypothesis. Acta Psychiatr Scand 1988; 78:257-75. functional and cognitive rates of decline during the 15. Guze BH , Hoffman JM , Mazziotta JC , Baxter L R , Phelps ME. course o f Alzheimer’s disease in order to realistically plan Positron emission tomography and familial Alzheimer’s disease: a for the growing demands on medical and social re pilot study. J Am Geriatr Soc 1992; 40:120-3. 16. Selkoc DJ. Aging, amyloid, and Alzheimer’s disease (editorial). N sources, to enable physicians to better inform patients Engl J Med 1989; 320:1484-7. and their families of the disease’s expected course, to 17. Candy JM , Oakley A E, Klinowski J, et al. Aluminosilicates and facilitate the recruitment of patients at definable stages senile plaque formation in Alzheimer’s disease. Lancet 1986;1: 3 5 4 - 7 . for clinical studies, and to apply drug therapy in a clini 18. McLean S. Assessing dementia (part 1): difficulties, definitions and cally and economically appropriate manner.57'58 differential diagnosis. Aust N Z J Psychiatry 1987; 21:142-74. To better care for their patients, family physicians 19. National Institute on Aging Consensus Development Panel. Dif ferential diagnosis o f dementing diseases. JAMA 1987; 258: will want to be aware o f ongoing clinical trials in which 3 4 1 1 -6 . their patients may participate. This information can be 20. McKhann G, Drachman D, Folstein M, Katzman R, Price D, obtained from the local chapters of their ADRDA. Fur Stadlan EM . Clinical diagnosis o f Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of De thermore, family physicians will need to develop diag partment of Health and Human Services Task Force on Alzhei nostic skills to identify patients with early disease, as the mer’s disease. Neurology' 1984; 3 4 :9 3 9 - 4 3 . most profound impact of these newer agents mav occur 21. Henderson VW, Finch CE. The neurobiolog)' of Alzheimer’s disease. J Neurosurg 1989; 7 0 :3 3 5 -5 3 . early on in the course o f Alzheimer’s disease. Until now 22. Martin RA, Guthrie R. Office evaluation o f dementia: how to

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arrive at a clear diagnosis and choose appropriate therapy Post oral physostigmine without lecithin improves memory in Alzhei grad Med 1988; 84:176-87. mer’s disease. J Am Geriatr Soc 1989; 3 7 :4 2 -8 . 23 Mulley GP. Differential diagnosis of dementia. BMJ 1986; 292: 44. Mohs RC, Davis BM, Johns CA, et al. Oral phvsostigminc treat ' 1416-8. ment of patients with Alzheimer’s disease. Am J Psychiatry’ 1985; 24 Skelton W P III, Skelton N K . Alzheimer’s disease. Postgrad Med 142:28-33. 1991;90:33-41. 45. Becker RE, Giacobini E. Mechanisms of cholinesterase inhibition 25 Kokmen E. Etiology, diagnosis, and management o f dementia in senile dementia of the Alzheimer type: clinical, pharmacological, Compr Ther 1 9 89; 1 5 :5 9 - 6 9 . and therapeutic aspects. Curr Trends Rev 1988; 12:163—95? 26. Winograd CH . The physician and the Alzheimer patient. In: Jarvik 46. Summers WK, Majovski LV, Marsh GM, Tachiki K, Kling A. Oral LF, Winograd C H , eds. Treatments for the Alzheimer patient. New York, NY: Springer Publishing Company, 1988:3-38. tetrahydroaminoacridine in long-term treatment of senile demen tia, Alzheimer type. N Engl J Med 1986; 31 5 :1 2 4 1 -5 . 27. Kluger A, Ferris SH. Scales for the assessment of Alzheimer’s 47. Davies B, Andreyves D, Stargatt R, Ames D, Tuckwell V, Davis S. disease. Psvchiatr Clin North Am 1991; 14:309-26. Tacrine in Alzheimer’s disease. Lancet 1 9 8 9 ;2 :1 6 2 -4 . 28. Ortof E, Crystal HA. Rate o f progression of Alzheimer’s disease. J 48. Gauthier S, Bouchard R, Lamontagne A, et al. Tetrahydroami- Am Geriatr Soc 1989; 37:511—4. noacridine-lecithin combination treatment in patients with inter 29. Folstein M F, Folstein SE, M cHugh PR. “Mini-mental state”: a mediate-stage Alzheimer’s disease. N Engl J Med 1990; 322: practical method for grading the cognitive state of patients for the 1272-6. clinician. J Psychiatr Res 1975; 1 2 :1 8 9 -9 8 . 49. Day’is KL, Thai LJ, Gamzu ER, et al. A double-blind, placebo- 30. 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607 The Journal of Family Practice, Vol. 37, No. 6, 1993